Recent investigations have revealed that glucagon plays a significant pathophysiologic role in glucose homeostasis and in diabetes. Four immunoreactive glucagon (IRG) species are present in plasma. This heterogeneity has been characterized only with regard to molecular size. The pancreas and gastrointestinal tract appear to be the source for circulating glucagon. The gastric species apparently is identical to pancreactic, but large amounts of non-identical glucagon-like immunoreactivity (GLI) are present elsewhere in the gut. The present proposal deals with efforts to more completely characterize the circulating IRG and GLI, particularly with regard to biological activity (adenyl cyclase activation), capacity to bind to specific glucagon receptors (liver membranes) and to site of origin. To investigate the contribution of gut "glucagons", a variety of surgical models have been devised: Isolated gastro-duodenal perfusions, eviscerations and partial eviscerations. Plasma IRG and GLI will be studied in these models. It is planned to evaluate nutritional and other controls of biosynthesis and secretion of enteric glucagons compared with pancreatic glucagons. Finally, studies will be focused upon elucidation of the characteristics and controls of specific glucagon receptors in animal and human diabetes in view of preliminary findings indicating a reduction in glucagon binding in human diabetic subjects.